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WNT pathway-driven anti-estrogen therapy resistance in breast cancer

Award Number: R01CA267549
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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WNT pathway-driven anti-estrogen therapy resistance in breast cancer - Project Summary The most aggressive cases of estrogen receptor-positive (ER+) breast cancers (BC) are diagnosed in young women (<50 years-of-age). This project is focused on an understudied, aggressive, and therapy-resistant form of ER+ BC that is characterized by predominantly ER+ luminal cancer cells interspersed with rare clusters of ER-negative stem/progenitor cells that express the basal cytokeratin-5 (CK5). Patients with this mixed ‘lumino- basal breast cancer’ (LBBC) phenotype represent a previously unrecognized population with unfavorable prognosis. These tumors are aggressive due to their inherent ER-independent endocrine escape pathway, which involves rapid expansion of the ER-/CK5+ cancer cell population in response to antiestrogen therapies. Our data reveal that LBBC shares the younger age distribution and aggressive features of basal-like BC, a BC subtype that is associated with pregnancy at early ages without breastfeeding – factors that are more prevalent among Black and poorer women and thus may help explain disparities in BC. Intriguingly, the basal-like features of LBBC are promoted by the pregnancy hormone progesterone and suppressed by the lactogenic hormone prolactin. Compelling pilot data indicates that progestins or anti-estrogens expand the therapy- resistant CK5+ stem/progenitor cell population in LBBC through a WNT11-PLZF-BCL6-dependent signaling network and is reversed by prolactin. The proposed studies will mechanistically test the general requirement of this WNT11-PLZF-BCL6 signaling network required for antiestrogen and progesterone-driven expansion of the CK5+ cell population and LBBC progression (Aim 1). Because the CK5+ cell population is often rare in untreated tumors, more robust diagnostic classifiers for LBBC than CK5 alone will be developed (Aim 2). Finally, efforts will explore the efficacy of targeted agents to disrupt this signaling network in vivo in preclinical models to provide rationale for new therapeutic strategies for LBBC (Aim 3). In sum, we will mechanistically validate a newly discovered pathway that promotes the therapy-resistant LBBC phenotype, develop better diagnostic methods, and explore therapeutic strategies to overcome endocrine resistance of these tumors. The project holds potential for high impact progress that can help reduce breast cancer mortality and morbidity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $549,696 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	3	4/14/2025	NON-COMPETING CONTINUATION	$494,727
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$54,969
														Subtotal = $549,696

Issue Date FY: 2024 ( Subtotal = $537,544 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	003	2	8/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$328,857
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	2	5/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$537,544
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Treatment Research	001	1	5/2/2024	NEW	$0
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Treatment Research	002	1	8/8/2024	NEW	-$328,857
														Subtotal = $537,544

Issue Date FY: 2023 ( Subtotal = $565,098 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Treatment Research	001	1	2/16/2023	NEW	$51,820
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Treatment Research	000	1	11/30/2022	NEW	$513,278
														Subtotal = $565,098

Grand Total All Awards = $1,652,338

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WNT pathway-driven anti-estrogen therapy resistance in breast cancer

Award Number: R01CA267549

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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